The present invention relates generally to compositions and methods useful for inhibiting the multiplication of human immunodeficiency virus-1 (HIV-1) in chronically infected patients, symptomatic or asymptomatic, thus minimizing progression to AIDS.
A variety of therapeutic methods are currently employed or under investigation to treat patients infected with human immunodeficiency virus (HIV-1). Certain approaches to HIV-1 treatment have focused on the transactivating (tat) gene of HIV-1, which produces a protein (Tat) essential for high levels of transcription of the virus. The tat gene and its protein have been sequenced and examined for involvement in proposed treatments of HIV (see, e.g., the documents cited in U.S. Pat. No. 6,525,179). Tat protein is released extracellularly, making it available to be taken up by other infected cells to enhance transcription of HIV-1 in the cells and to be taken up by noninfected cells, altering host cell gene activations and rendering the cells susceptible to infection by the virus. Uptake of Tat by cells is very strong, and has been reported as mediated by a short basic sequence of the protein (S. Fawell et al., 1994 Proc. Natl. Acad. Sci., USA, 91:664-668).
Both monoclonal and polyclonal antibodies to Tat protein have been readily produced in animals and shown to block uptake of Tat protein in vitro and such monoclonal or polyclonal antibodies to Tat protein added to tissue culture medium have attenuated HIV-1 infection in vitro (see, e.g., documents cited in U.S. Pat. No. 6,524,582).
Prior scientific publications and patent publications by one of the present co-inventors (e.g., G. Goldstein, 1996 Nature Med., 2:960; G. Goldstein, 2000 Vaccine, 18:2789; International Patent Publication No. WO 95/31999, published Nov. 30, 1995; International Patent Publication No. WO 99/02185, published Jan. 21, 1999; International Patent Publication No. WO 01/82944, published Nov. 8, 2001; U.S. Pat. Nos.: 5,891,994; 6,193,981; 6,399,067; 6,524,582; and 6,525,179; US Published Patent Application Nos. US 2003/0,166,832 and US 2003/0,180,326) refer to antibodies to certain epitopes on HIV-1 Tat protein as AIDS vaccine and therapeutic agents.
For example, these publications refer to antibodies which specifically bind to an epitope located within the “HIV-1 Tat Epitope 1” sequence spanning Tat amino acid residues 4-12, as follows: Val-Asp-Pro-X7-Leu-Y9-Pro-Trp-Z12- SEQ ID NO: 1, wherein X7 is Arg, Lys, Ser or Asn, Y9 is Glu or Asp, and Z12 is Lys or Asn, and compositions combining this antibody with other antibodies to HIV-1 Tat. These publications also refer to another antibody composition containing isolated antibodies which bind specifically to an epitope located within the “HIV-1 Tat Epitope 2” sequence spanning Tat amino acid residues 41-50 of the formula -Lys-X42-Leu-Gly-Ile-Ser-Tyr-Gly-Arg-Lys- SEQ ID NO: 2, where X42 is Gly or Ala. Additionally, these publications refer to isolated antibodies which bind specifically to an epitope located within the “HIV-1 Tat Epitope 3” sequence spanning Tat amino acid residues 56-62 of the formula -Arg-Arg-X58-Z59-A60-Y61-Ser- SEQ ID NO: 3, wherein X58 is Ala, Pro, Ser, or Gln, Z59 is Pro or His, A60 is Gln or Pro, and Y61 is Asp, Asn, Gly or Ser, or to an epitope located within the “HIV-1 Tat Epitope 4” sequence spanning Tat amino acid residues 62-73 of the formula -Ser-Gln-X64-His-Gln-Y67-Ser-Leu-Ser-Lys-Gln-Pro- SEQ ID NO: 4, wherein X64 is Asn or Thr, and Y67 is Ala or Val.
Compositions formed of combinations of these antibodies, particularly combinations of an antibody to one Epitope 1 variant with one or more antibodies that each binds a different Epitope 1 variant, and further combinations of such Epitope 1 antibodies and Epitope 2 antibodies, among other combinations are able to bind a large number of Tat variant sequences characteristic of the multiple strains and subtypes of HIV-1, both B and non-B clades. These antibody compositions are designed to inhibit HIV-1 infectivity during initial infection and/or lower viral load post sero-conversion, thus delaying progression to AIDS. Further, these resulting compositions or mixtures of such anti-Tat antibodies are advantageous as treatments for many strains and subtypes of the virus, thus obviating the need for different, and strain-specific, therapeutic agents.
Despite the growing knowledge about HIV-1 disease progression, there remains a need in the art for the development of compositions and methods for treatment of chronic infection with HIV-1, to retard or prevent progression of the infection to the generally fatal, full-blown AIDS.